Abstract
Methylglyoxal (MGO)-induced cellular apoptosis, oxidative stress, inflammation, and AGE formation are specific events that induce vascular endothelial cell (EC) toxicity in endothelial dysfunction (ED). MGO accumulates quickly in various tissues and plays a prominent role in the pathogeneses of several diabetic complications. Unbalanced angiogenesis is a gateway to the development of diabetic complications. EC apoptosis and autophagy work together to regulate angiogenesis by interacting with different angiogenic factors. In addition to understanding the deep mechanism regarding MGO-dependent autophagy/apoptosis may provide new therapeutic applications to treat diabetes and diabetic complications. Therefore, the present study aimed to investigate the regulatory effects of MGO-induced autophagy and apoptosis on angiogenesis in HAoEC and to elucidate the molecular mechanisms to discover new target base therapy for diabetes and diabetic complications. In MGO-stimulated HAoEC, protein expression was identified using a western blot, autophagosomes were observed by bio-transmission electron microscopy (TEM), and cell autophagic vacuoles and flux were measured using a confocal microscope. We found that MGO significantly induced autophagy, declined the pro-angiogenic effect, decreased proliferation, migration, and formation of tube-like structures, and increased autophagic vacuoles, flux and autophagosomes in the HAoEC in a dose-dependent manner. We observed that MGO-induced autophagic cell death and inhibited the ROS-mediated Akt/mTOR signaling pathway. MGO also triggered apoptosis by elevating the cleaved caspase-3 to Bax/Bcl-2 ratio and through activation of the ROS-mediated MAPKs (p-JNK, p-p38, and p-ERK) signaling pathway. Collectively, these findings suggest that autophagy and apoptosis inhibit angiogenesis via the ROS-mediated Akt/mTOR and MAPKs signaling pathways, respectively, when HAoEC are treated with MGO.
Highlights
Diabetes mellitus (DM) is a major social problem[1]
In this study, it was hypothesized that MGO may exert similar effects on human dermal microvascular EC (HDMEC) and Human aortic EC (HAoEC)
HAoEC, human umbilical vein EC (HUVEC), and HDMEC were treated with several concentrations of MGO (0.6, 0.8, and 1.0 mM) for 1 and 24 h
Summary
Diabetes mellitus (DM) is a major social problem[1]. A previous study reported that the prevalence of DM is on the rise, and 425 million patients live with diabetes worldwide and are expected to increase by 47% to 629 million in 20452. Targeting autophagy/ apoptosis in relation to other causative factors may provide new therapeutic applications to ameliorate diabetic complications. The accumulation of MGO has been associated with the pathogenesis of diabetes, vascular complications, and several age-related chronic inflammatory diseases such as cardiovascular disease, Parkinson’s diseases, and Alzheimer’s disease[10,11]. A recent report demonstrated that MGO can cause ED, microvascular complications (nephropathy, retinopathy, and neuropathy), macrovascular (atherosclerosis, heart failure, impaired revascularization, and wound healing), obesity, β-cells toxicity, insulin resistance, and age-related diseases (hypertension, cancer, and central nervous system; dementia, Parkinson’s disease, schizophrenia, and anxiety disorders)[11]. Aminoguanidine (AG) has been reported to prevent diabetic complications by preventing the AGE formation and decreasing plasma and aortic MGO levels[14,15,16]. Aminoguanidine was used to confirm the underline mechanism associated with MGO to treat diabetes
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